The present invention relates to a novel salt useful in therapy. More specifically the present invention relates to 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate, to processes for its preparation, to its uses, and to compositions containing it. The present invention also relates to novel non-hydrated polymorphs of the free base.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline has the formula 
and is disclosed in WO 98/30560 (see Example 19) as being useful in the treatment of benign prostatic hyperplasia. The application refers in general terms to pharmaceutically acceptable salts and mentions the hydrochloride, hydrobromide and phosphate salts.
Unfortunately, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline displays some disadvantageous physical properties. It is now known to occur in a number of different forms. In some cases, its aqueous solubility is rather low and it is difficult to prepare reproducibly in the same form, sometimes being obtained in a hydrated form. In addition, it has been found that some forms of the free base are rather hygroscopic. These properties are disadvantageous for the development of a drug substance because, in particular, a consistent grade of material must be reproducibly manufactured in order to satisfy regulatory requirements.
There is now provided the mesylate salt of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline having the formula 
This substance has a number of unexpected advantages over the free base and it has surprisingly been found to have a unique combination of properties which make it ideal for development as a drug substance.
Those skilled in the art will appreciate that xe2x80x9cmesylatexe2x80x9d is an alternative term for xe2x80x9cmethanesulfonatexe2x80x9d.
The mesylate salt has a high melting point, and is a crystalline solid which does not display any hydrated or solvated forms. It is isomorphic, i.e. it exists in a single polymorphic form, and exhibits good stability over a wide range of conditions, e.g. high light intensity. It has acceptable solubility and dissolution characteristics, and can be economically prepared and processed to provide suitable solid dosage forms of the drug. Its hygroscopicity is substantially lower than the free base (tested as its 198xc2x0 C. melting point polymorph) over a wide range of relative humidity. The mesylate salt is mono-morphic and does not form hydrates; both of these features represent advantageous properties of the mesylate salt in particular.
Tables 1 to 3 below indicate the physical properties of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate and some free base forms.
The present invention also includes the substantially pure anhydrous crystalline forms of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (the free base). These anhydrous polymorphs are designated Form A, Form B, Form C, and Form E in Table 4 below. Form D, which is presented for comparison, is the hydrated form and exists as a dihydrate.
The term xe2x80x9csubstantially purexe2x80x9d used above means that a sample of the relevant anhydrous crystalline form contains more than 90% of a single polymorphic form, preferably more than 99% of a single polymorphic form.
On dehydration, the hydrated form (Form D) becomes amorphous.
The anhydrous polymorphic forms of the invention are also significantly less hygroscopic than the hydrated free base form. Of these, Forms B and E are preferred on account of their high melting points and low hygroscopicity. Form E is most preferred.
It is now believed that the solid form of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline produced originally following the procedure of WO 98/30560 (see Example 19) was a mixture of Forms B and E, probably in the ratio 1:1 (based on a differential scanning calorimetry experiment showing sharp endotherms at 220 and 227xc2x0 C.). Following the creation of the most stable Form E in pure form, it is likely that this form will be produced predominantly in the future when repeating the above preparation of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline.
Also included within the scope of the present invention are radiolabelled derivatives, other isotopic forms and tautomers of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in one of its free base polymorphic forms or as the mesylate salt possesses pharmacological activity in animals. It may be used in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of greatest interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt to a patient suffering from such a disorder.
According to a further aspect of the invention, there is provided 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)-quinazoline in the form of the anhydrous free base or the mesylate salt for use as a pharmaceutical; and for use in the treatment of benign prostatic hyperplasia.
According to a further aspect of the invention, there is provided the use of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)-quinazoline in the form of the anhydrous free base or the mesylate salt in the manufacture of a medicament for the treatment of benign prostatic hyperplasia.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
Hence, according to a further aspect of the invention, there is provided a pharmaceutical formulation including 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The formulation will preferably contain less than 50% by weight of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in a free base polymorphic form or as the mesylate salt.
For example, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications. Oral administration is of particular interest. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt may also be administered via intracavernosal injection.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrastemally, intracranially, intramuscularly or subcutaneously, or may be administered by infusion techniques. It is best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt will usually be from about 0.01 to 10 mg/kg (in single or divided doses) and preferably about 0.01 to 0.5 mg/kg, administered from 1 to 4 times a day.
Thus tablets or capsules of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt may contain from about 0.1 mg to 500 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can also be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HEFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 20 xcexcg to 4 mg of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20 xcexcg to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt may also be transdermally administered, for example, by the use of a skin patch. It may also be administered by the ocular route, particularly for treatment of the eye.
For ophthalmic use, it can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, it may be formulated in an ointment such as petrolatum.
For application topically to the skin, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The invention further provides a process for the preparation of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline mesylate, as defined above, which comprises the addition of methanesulphonic acid to a suspension or solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline of the formula 
in a suitable solvent, and collection of the precipitated solid.
Preferred features of the process include:
(a) the solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is maintained at a temperature above room temperature before the addition of the methanesulphonic acid; and
(b) the solvent used is a mixture of butanone and water, for example a 10:1 by volume mixture of butanone and water.
The process may be defined more particularly as a process comprising the steps of:
(a) heating a suspension of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in butanone/water to reflux;
(b) adding butanone/water until a solution is achieved;
(c) cooling the solution;
(d) adding methanesulfonic acid; and
(e) collecting the resulting solid by filtration.
In the above processes, it is preferred that the 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is present as Form E, although some of the desired product should result regardless of the starting form.
The formulations of the invention may also contain a human 5-xcex1 reductase inhibitory compound [see International Patent Application WO-A-95/28397], or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt could be presented in a pharmaceutical pack also containing a human 5-xcex1 reductase inhibitory compound as a combined preparation for simultaneous, separate or sequential use.
References herein to treatment include curative, palliative and prophylactic treatment.
The four anhydrous polymorphs of the free base which have been isolated have been designated Forms A, B, C and E. These polymorphic forms were characterised by powder X-ray diffraction (PXRD), together with the mesylate salt.
The powder X-ray diffraction patterns were determined using a SIEMENS D5000 powder X-ray diffractometer fitted with an automatic sample changer, a thetaxe2x80x94theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. The samples were prepared for analysis by packing the powder into 12 mm diameter, 0.25 mm deep cavities that had been cut into silicon wafer specimen mounts. Each specimen was rotated whilst being irradiated with copper K-alpha1 X-rays (wavelength=1.5406 Angstroms) with the X-ray tube operated at 40 kV/40 mA. The analyses were performed with the goniometer running in step-scan mode set for a 5 second count per 0.02xc2x0 step over a two theta range of 2xc2x0 to 55xc2x0. The peak intensities are summarised in Table 5. In Table 5, xe2x80x9cAngle 2-Thetaxe2x80x9d is related to the interplanar spacing of the crystal, and the intensity is given as a percentage of the greatest peak (I/Ii). The individual polymorphic forms and the mesylate salt may be characterised by reference to the peak intensities of greater than 50%, and more preferably by the peaks having intensities greater than 20%.
Differential scanning calorimetry (DSC) was performed using a Perkin Elmer DSC-7 machine fitted with an automatic sample changer. Approximately 2 mg of each sample was accurately weighed into a 50 microlitre aluminium pan and crimp sealed with a perforated lid. The samples were heated at 20xc2x0 C./minute over the range 40xc2x0 C. to 300xc2x0 C. with a nitrogen gas purge. The thermal events are summarised in Table 6, and may be used to characterize the free base forms and mesylate salt.
The water content of the hydrated form of the free base (Form D) at ambient conditions is commonly of the order of 9 to 10% (w/w). This is equivalent to 2.5 to 2.8 moles of water per mole of the free base. The water content at 90% RH was found to be 12.8% (w/w), this is equivalent to 3.6 moles of water, only 2 moles of which were found to represent bound water. The first mole was lost below 5% RH the second retained down to 1% RH see FIG. 11. It is likely that extended storage of the hydrated form below about 18% RH would result in dehydration. Furthermore, removal of the crystalline water results in the loss of the crystal lattice, the product being predominantly amorphous. This highlights a potential problem in using the conventional hydrated form in manufacturing a pharmaceutical formulation. Dehydration was observed on thermal analysis as a broad double endotherm at 97/113xc2x0 C. (See FIG. 8)